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Publication Number
US-9957296-B2
Publication Date
2018-05-01
Expiration Date
Abstract
The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production.
Core Innovation
The disclosure relates to peptidomimetic macrocycles and peptidomimetic macrocycle compound defined by Formula (I), including variable amino-acid residues and a macrocycle-forming linker. It describes design considerations intended to stabilize an α-helix, maintain intrahelical interactions and hydrogen bonding, and support structural stability, target affinity, proteolytic resistance, and desired intrahelical interactions.
The disclosure describes peptidomimetic macrocycles and methods of synthesizing them by incorporating an alkyne moiety into a peptide together with an amino acid moiety defined by Formula IIa/IIb or a broad substitution scheme for multiple substituents, including R2, Q, T, K, R3, R4, R5, R6, R8, R10, and R11. The resulting peptidomimetic macrocycle comprises an additional macrocycle.
The document further refers to solid-phase synthesis of azide/alkyne-containing peptidomimetic precursors and macrocyclization using Cu reagents or Ru(II)-catalyzed macrocyclization reagents such as Cp*RuCl(PPh3)2 and [Cp*RuCl]4. It also provides exemplary peptidomimetic macrocycles including triazole-linked peptidomimetic macrocycles, with structural parameters such as helix-turn ranges and ring-size ranges linked to α-helical stabilization and macrocycle performance.
Claims Coverage
Independent claim coverage centers on synthesizing a peptide that incorporates an alkyne moiety and a broadly defined amino acid moiety, then macrocyclizing the peptide to form a peptidomimetic macrocycle that comprises an additional macrocycle. Dependent claims add α-helix, helix-turn range, ring-size range, and specific R2 selection features.
Alkyne-containing peptide with broadly defined amino-acid substitution scheme
Synthesizing a peptide that incorporates an alkyne moiety and an amino acid moiety defined by a formula, with substitution schemes including R2, Q, T, K, R3, R4, R5, R6, R8, R10, and R11, and protecting groups suitable for peptide synthesis.
Macrocyclization to form a peptidomimetic macrocycle comprising an additional macrocycle
Macrocyclizing the peptide so that the resulting peptidomimetic macrocycle comprises an additional macrocycle.
α-helix macrocycle constraint
Limiting the peptidomimetic macrocycle to include an α-helix.
α-helix helix-turn range
Limiting the α-helix to comprise from 1 turn to 5 turns.
Ring-size range for peptidomimetic macrocycle
Defining that the peptidomimetic macrocycle comprises a ring of about 29 atoms to about 37 atoms.
R2 substituent selection
Selecting R2 as hydrogen or methyl.
Overall, the claims focus on forming an alkyne-containing peptide with a broadly defined amino-acid moiety, followed by macrocyclization to yield a peptidomimetic macrocycle that includes an additional macrocycle. The dependent claims further narrow the structure with α-helical and ring-size constraints and specified R2 choices.
Stated Advantages
Increased α-helical stability.
Thermal stability.
Protease resistance.
Cell penetration.
Enhanced cellular uptake via lipidation and PEGylation.
Improved target affinity.
Improved bioavailability/blood circulation and pharmacokinetics are discussed as properties associated with the design rationale.
Documented Applications
Performance evaluation and characterization of the described triazole-based peptidomimetic macrocycle systems using circular dichroism (CD) and NMR, including discussion of proteolytic degradation and cell penetration.
Binding assessed via fluorescence polarization (FPA), including examples referencing acceptor proteins.
Use of peptidomimetic macrocycles containing target-derived peptide motifs, including BCL-2 family BH3 segments and p53/MDM2 α-helical regions.
Targets associated with GPCR peptide ligands, including Angiotensin II, Bombesin, Bradykinin, C5a, C3a, and α-melanocyte stimulating hormone.
Therapeutic context and exemplified therapeutic use areas, including applications in soft tissue sarcomas and as a chemotherapy adjuvant.
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